There is increasing evidence that in addition to the well-recognized complications of type 2 diabetes mellitus (T2DM), including retinopathy, nephropathy, neuropathy, and vascular disease, these patients also have an elevated fracture risk. Paradoxically, T2DM patients have relatively preserved or even increased areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA). This clinically important discrepancy has not been adequately explained, although there is now considerable evidence that critical aspects of bone quality, distinct from aBMD, contribute to fracture risk in patient with T2DM. However, this fundamental issue has remained unresolved because of difficulties in measuring critical components of bone quality non- invasively. Thus, we have developed experience with innovative technologies, including high-resolution peripheral quantitative computed tomography (HRpQCT), to evaluate the contributions of bone microarchitecture to fracture risk. Importantly, the skeleton is 80% cortical bone, and of all the trabecular and corticl bone microarchitectural parameters evaluated to date using HRpQCT in T2DM patients, increased cortical porosity has emerged as the most consistent abnormality. Material composition is another key component of bone quality, but until recently, bone material properties could not be safely assessed in vivo in humans. However, using the OsteoProbe(r), a novel bone microindentation device that provides an in vivo index of cortical bone material properties (bone material strength index [BMSi]), we recently demonstrated that postmenopausal women with T2DM have a significant decrease in BMSi compared to matched non-diabetic women. In this proposal, we will assess key aspects of bone quality, including BMSi and cortical porosity, in patients with T2DM, where clinical assessment of fracture risk requires urgent refinement. Since 80% of all fractures are non-vertebral and occur at mainly cortical sites, we will focus on non-vertebral fragility fractures. Thus, our Specific Aims are: Ina case-control study involving 400 postmenopausal women and men age ? 50 yrs, test the hypothesis that patients with T2DM and non-vertebral fragility fractures have reduced BMSi and increased cortical porosity compared to non-fracture T2DM controls (Aim 1a); evaluate the relationship of other, well recognized diabetic complications (i.e., retinopathy, nephropathy, neuropathy, and vascular disease) to our measured components of bone quality (Aim 1b); and, using a combination of bone quality variables, evaluate the extent to which fracture risk prediction can be improved beyond that provided by DXA (Aim 1c). Further, in a longitudinal study of 150 T2DM and 150 non-diabetic controls, we will test the hypothesis that patients with T2DM have a greater deterioration in BMSi and in cortical porosity over 3 yrs as compared to non-diabetic controls (Aim 2a); and identify the hormonal and biochemical determinants of changes in these key parameters of cortical bone quality and evaluate the possible relationship between existing diabetic complications and skeletal deterioration over time in the T2DM patients (Aim 2b).